Carriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15–20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of CDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC in p16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients’ surveillance. In a recent genome-wide association study (GWAS), rs36115365-C was found to significantly modify risk of PC and melanoma in the European population. This SNP is located on chr5p15.33 and has allele-specific regulatory activities on TERT expression. Herein, we investigated the modifying capacities of rs36115365-C on PC and melanoma in a cohort of 283 p16-Leiden carriers including 29 diagnosed with PC, 171 diagnosed with melanoma, 21 diagnosed with both PC and melanoma and 62 with neither PC nor melanoma. In contrast to previously reported findings, we did not find a significant association of PC risk with risk variant presence as determined by Generalized Estimating Equations (GEE) modelling. Interestingly, carrier-ship of the risk variant had a significant protective effect for melanoma (OR − 0.703 [95% CI − 1.201 to − 0.205], p = 0.006); however, the observed association was no longer significant after exclusion of probands to assess possible influence of ascertainment. Collectively, genetic modifiers for the prediction of PC and melanoma risk in p16-Leiden carriers remain to be determined.

中文翻译：

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评估位于TERT / CLPTM1L多癌风险区域的单个SNP作为荷兰CDKN2A突变携带者中胰腺癌和黑色素瘤风险的遗传修饰因子。

CDKN2A中病原体变异的携带者终身罹患黑色素瘤的风险为70％，而罹患胰腺癌（PC）的风险为15–20％。在荷兰，CDKN2A（p16-Leiden突变）外显子2中19 bp的缺失是大多数遗传性黑色素瘤病例的原因。临床经验表明p16-Leiden中黑色素瘤和PC发生的变异性家庭。因此，环境和遗传因素均可改变罹患癌症的风险，这表明遗传修饰剂的鉴定可改善患者的监测。在最近的全基因组关联研究（GWAS）中，发现rs36115365-C可以显着改变欧洲人群中PC和黑色素瘤的风险。该SNP位于chr5p15.33上，对TERT表达具有等位基因特异性调控活性。在本文中，我们研究了rs36115365-C在283 p16组中对PC和黑色素瘤的修饰能力-Leiden携带者包括29例诊断为PC的患者，171例诊断为黑色素瘤，21例同时诊断为PC和黑色素瘤以及62例既没有PC也没有黑色素瘤。与先前报道的发现相反，我们没有发现PC风险与通过广义估计方程（GEE）建模确定的风险变量存在显着关联。有趣的是，风险变异的携带者对黑素瘤具有显着的保护作用（OR-0.703 [95％CI-1.201至-0.205]，p = 0.006）；但是，在排除先证者以评估确定性可能影响后，观察到的关联不再显着。总的来说，用于预测p16-Leiden携带者中PC和黑色素瘤风险的遗传修饰剂仍有待确定。